Nadal is still only 26, but the withdrawals raise questions about the future of a player who has had recurring knee problems in the past.

His 11 Grand Slam titles include a record seven on the red clay of the French Open, yet his hard-charging, hard-hitting style of play takes a toll on his body, particularly his knees.

Roger Federer, in contrast, has played in every Grand Slam tournament since the start of 2000, a streak of 51 in a row.

"Well, not a surprise, because I wrote him and he told me it wasn't looking good at all," Federer said after his opening match of the Western & Southern Open. "I kind of knew, saw it coming. But obviously when it's official, it's disappointing for tennis, there's no doubt about it. I would love to have him in the draw. In particular, sort of the 12 days before the Open, you figure he might still have time to fix what he has to fix to get ready. If he pulls out that early before the Open, it must be something serious.

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"That's what is sort of scary. There is obviously the whole debate going on if he is going to come back for this year. I hope he will. He's definitely got some more weeks off now because of it. I hope in hindsight this is a very smart decision by him. But it's obviously a big blow and disappointing news for the tennis world."

In 2009, Nadal missed Wimbledon because of aching knees shortly after falling in the round of 16 at the French Open - the only time in eight appearances he hasn't won at Roland Garros. He was just the second men's champion in 35 years to decline to defend his title at the All England Club.

But Nadal eventually came back stronger than ever from that layoff. After failing to reach the final at the 2009 U.S. Open and 2010 Australian Open, he won the French to start a run of three straight major titles, capped by completing the career Grand Slam at Flushing Meadows.

Nadal's absence immediately leaves a trio of heavy favorites at the last Grand Slam event of the year: defending champion Novak Djokovic; five-time US Open winner and currently top-ranked Federer; and 2008 US Open runner-up Andy Murray, who won the gold medal in singles at the London Games by beating Federer in the final.

"My excitement is always the same when I am approaching any Grand Slam. Obviously it's the biggest tournaments we have in sport," Djokovic said after winning at the Western & Southern Open outside Cincinnati. "Yes, the fact is that tennis is going to lose a little bit because of Rafa not being there and playing, because he's somebody that has made a history of this sport. We all know how good he is and how popular he is."

Nadal lost in the US Open final to Djokovic last year, part of a stretch of three straight defeats to the Serb in championship matches at major tournaments. But he seemed to be closing the gap, and at Roland Garros in June, he beat Djokovic in the final for his record seventh title there.

Then came the stunning loss at Wimbledon, and Nadal hasn't played since.

On 28 June, 100th-ranked Lukas Rosol upset him in the second round at the All England Club. Shortly after that defeat, Nadal canceled a scheduled charity match against Djokovic in Spain, citing tendon problems in his left knee.

He also pulled out of the hard-court warm-up tournaments in Toronto and Cincinnati.

The two-week US Open begins on 27 August.

"Rafa has informed us that he will not be ready to compete at the U.S. Open this year and has withdrawn from the tournament," tournament director David Brewer said in a statement issued Wednesday. "We hope to see him back on the court soon and look forward to his return to New York next year."